News & Comment

Understanding how the complex molecular mechanisms of the brain can be blighted, and what their role is in neurological disorders, can be an intricate task. The basis of mood alterations and how humans react to a damaged or altered brain circuit can provide clues for new therapies to target the root of these neurological glitches. In 'Bedside to Bench', Daniel Weinberger and Caroline Zink discuss how people with anorexia nervosa showed a connection between self starvation and motivational value—an opposite perspective to the traditional idea linking the absence of joy to the symptoms of this disorder and a new paradigm for developing the appropriate treatments. In 'Bench to Bedside', Dennis Charney and James Murrough peruse how the antidepressant action of ketamine in rats—a neurotrophic effect—can explain the rapid reduction in depression observed in the clinic with this drug. The receptors and signaling cascades involved may be used to develop therapies that may further enhance this rapid beneficial effect.

In Crohn's disease, immune damage to the gut wall is both induced and modified by the gut microflora, challenging researchers to solve the maze of interactions exploitable for therapeutic benefit. Whether these microbial 'guests' are worsening or helping in this scenario is still open to debate. In 'Bench to Bedside', Warren Strober highlights mice studies showing that certain microbes in the gut have a protective role promoting a shift towards an increased regulatory response that protects from recurrence of the disease. In 'Bedside to Bench', Thomas MacDonald examines how human studies using strategies to block soluble proinflammatory cytokines—despite solid supporting data from animal models—have shown disappointing results compared with therapies that neutralize soluble cytokines but also deplete proinflammatory cells, calling into question whether targeting a single soluble cytokine will ever be useful to treat people with Crohn's disease.

Much of how the human host responds to a tumor and to anticancer therapy is still not fully fleshed out. The cytokines and other mediators involved in this response may be both allies and enemies in the quest for more effective treatments or even a cancer cure. In 'Bedside to Bench', Robert Kerbel and John Ebos discuss recent human studies in healthy individuals and people with minimal residue or no disease showing release of host-derived cytokines after antiangiogenic therapy. The increase in proangiogenic factors such as VEGF and PIGF and other cytokines involved in metastasis and tumor repopulation in a host may threaten therapeutic success but may also suggest new prognostic markers and other treatment strategies. In 'Bench to Bedside', Michael Karin and Florian Greten peruse how using JAK2 inhibitors to block STAT3 in tumors could halt cancer progression. JAK2 inhibitors, already being tested in clinical trials to treat myeloproliferative diseases, may also prove valid as anticancer drugs.

The complexity of human metastatic cancer is difficult to mimic in mouse models. As a consequence, seemingly successful studies in murine models do not translate into success in late phases of clinical trials, pouring money, time and people's hope down the drain. In 'Bedside to Bench', Isaiah Fidler and Lee Ellis discuss crucial parameters in cancer growth and therapy and emphasize the disparity between studies in humans and mice. In 'Bench to Bedside', Terry Van Dyke shows how pancreatic tumors developed de novo in the organ site in mice can explain therapy failure in people with cancer and serve as a model to test new drugs.

Macrophages engulf microbes and cellular debris to protect us from disease and help repair wounded tissues. In cancer, they also infiltrate the tumor, but studies in humans and mice now uncover more sinister roles for these immune cells in cancer. In 'Bedside to Bench', Christiana Ruhrberg and Michele De Palma scrutinize a clinical study where the presence of macrophages correlates with a high risk of disease progression in people with Hodgkin's lymphoma, indicating a clinical value of macrophages as biomarkers of survival. The authors also emphasize how characterizing of the mechanisms by which subpopulations of macrophages promote tumor cell motility and angiogenesis might help in the development of antiangiogenic therapies to stop tumor progression. In 'Bench to Bedside', Joseph Qualls and Peter Murray examine a study that shows how stopping migration of macrophages into the tumor can impair tumor regrowth after radiation treatment.

Basic research on the mechanisms of blood coagulation and the inflammatory response during tissue damage has revealed new potential targets for antithrombotic drugs. In 'Bench to Bedside', Charles T. Esmon examines three such studies, which offer the possibility of developing badly needed drugs that could block thrombosis without increasing the risk of hemorrhage. Esmon also raises the possibility that the new research could help explain why distal injury may contribute to protection of organs such as the heart, a process called 'remote conditioning'. In 'Bedside to Bench', Christian Weber takes a closer look at a clinical trial of remote ischemic conditioning, involving intermittent periods of occlusion and reperfusion on the arm. He examines evidence that cross-talk between cytokine and opioid receptors may underlie the effectiveness of this technique in protecting the heart from damage.

Numerous factors can contribute to sudden cardiac death, from underlying disease after myocardial infarction to genetic variants that can claim young lives. In 'Bedside to Bench', Stanley Nattel examines recent clinical studies suggesting that a particular type of readout on an electrocardiogram (ECG) may increase the risk of the condition. This ECG 'variant' is relatively common and was previously thought to be benign. In 'Bench to Bedside', Gordon Tomaselli and Andreas Barth take a look at studies at the bench examining how oxidative stress may promote sudden cardiac death.

Much can go wrong during the nine-month journey from single cell to birth—with infertility stopping the process as it begins and premature birth completing it before its time. These two major problems in reproductive biology are examined by Bruce D. Murphy, Yasushi Hirota, Jeeyeon Cha and Sudhansu K. Dey. In 'Bench to Bedside', Murphy analyzes studies showing how a single gene, FOXL2, may mediate many processes required for fertility. In 'Bedside to Bench', Dey and colleagues take a look at conflicting clinical findings testing progesterone as a therapy for premature birth: they conclude that much more work needs to be done at the bench, particularly in developing mouse models of parturition, before clinicians can successfully intervene to prevent birth from occurring prematurely.

Blood transfusion saves many lives but carries the risk of injury, such as severe damage to the lungs. In 'Bedside to Bench', Janet S. Lee and Mark T. Gladwin examine the implications of clinical studies assessing such damage. The risk of injury seems to increase with the number of units transfused and may be greater with blood that has been stored longer. Researchers have yet to understand why, but several mechanisms are under scrutiny. In 'Bench to Bedside', Paul S. Frenette and Narla Mohandas discuss recent studies pinpointing a trigger—a specific antigen on neutrophils for a severe form of transfusion-related acute lung injury (TRALI). The findings could lead to new ways to diagnose TRALI and identify people at risk.

Thinking about how asthma and allergic diseases arise is undergoing several shifts. In 'Bedside to Bench', Clare M. Lloyd and Sejal Saglani examine how recent human studies are putting the focus on the epithelium as a major contributor to asthma. The findings shift the emphasis away from the T helper type 2 immune response, and call into question the utility of current animal models of the disease. Although asthma and other allergic disorders are known to have origins in infancy, some researchers are looking even earlier, to effects in utero and before conception. In 'Bench to Bedside', Catherine Hawrylowicz and Kimuli Ryanna highlight animal studies that outline some of the effects of the maternal environment, and they examine the potential implications for prevention of disease.